TY  - JOUR
AU  - Oberländer, Kristin
AU  - Pruunsild, Priit
AU  - Koch, Philipp
AU  - Yan, Jing
AU  - Szafranski, Karol
AU  - Bading, Hilmar
TI  - Inhba, Homer1 and Bdnf are major targets of transcriptomic dysregulation by neurodegenerative disease-associated excitotoxic NMDA receptor signaling.
JO  - Communications biology
VL  - 8
IS  - 1
SN  - 2399-3642
CY  - London
PB  - Springer Nature
M1  - DZNE-2025-01342
SP  - 1743
PY  - 2025
AB  - Synaptic activity-regulated gene expression supports neuroprotection, plasticity, and memory. The transcription factor CREB is central to these processes. It is activated by synaptic NMDA receptors but inactivated by excitotoxic extrasynaptic NMDAR (esNMDAR) signaling. Using primary hippocampal neurons, we modeled neurodegeneration and found that esNMDAR activation, which causes CREB shut-off and inactivation of the ERK/MAPK-ELK1/SRF pathway, extensively distorted control of synaptic activity over transcription. This resulted in the suppression of key neuroprotective genes, in particular Inhba and Bdnf, but also of genes involved in synaptic function (Homer1, Btg2, Mir132, Mir212) and transcription factor genes (Atf3, Egr1, Fos, Npas4). In a Huntington's disease (HD) mouse model, treatment with memantine or targeting the NMDAR/TRPM4 complex with FP802 restored gene expression, notably Inhba, Homer1 and Bdnf, and attenuated the decrease of the HD disease marker Ppp1r1b (DARPP-32). These findings identify esNMDAR-driven transcriptional dysregulation as a key pathomechanism in neurodegenerative disease, supporting inhibition of esNMDAR-signaling as a promising therapeutic approach.
KW  - Animals
KW  - Brain-Derived Neurotrophic Factor: genetics
KW  - Brain-Derived Neurotrophic Factor: metabolism
KW  - Receptors, N-Methyl-D-Aspartate: metabolism
KW  - Receptors, N-Methyl-D-Aspartate: genetics
KW  - Homer Scaffolding Proteins: genetics
KW  - Homer Scaffolding Proteins: metabolism
KW  - Mice
KW  - Signal Transduction
KW  - Transcriptome
KW  - Neurodegenerative Diseases: metabolism
KW  - Neurodegenerative Diseases: genetics
KW  - Hippocampus: metabolism
KW  - Neurons: metabolism
KW  - Huntington Disease: genetics
KW  - Huntington Disease: metabolism
KW  - Gene Expression Regulation
KW  - Disease Models, Animal
KW  - Male
KW  - Mice, Inbred C57BL
KW  - Brain-Derived Neurotrophic Factor (NLM Chemicals)
KW  - Receptors, N-Methyl-D-Aspartate (NLM Chemicals)
KW  - Homer Scaffolding Proteins (NLM Chemicals)
KW  - Homer1 protein, mouse (NLM Chemicals)
KW  - Bdnf protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41339520
DO  - DOI:10.1038/s42003-025-09074-9
UR  - https://pub.dzne.de/record/282582
ER  -